tbuckley/cabot-search huggingface dataset:
Reducing Prostate Cancer Overdiagnosis
Authors: Roman Gulati
Journal: New England Journal of Medicine (2022)

Prostate cancer is a major public health problem, having caused more than 375,000 deaths worldwide in 2020.1 One of the main tools available to lessen this burden is prostate-specific antigen (PSA) screening. Large, randomized trials have shown that PSA screening significantly reduces the risk of death from prostate cancer.2 However, PSA screening also incurs substantial harms, most importantly overdiagnosis — the diagnosis of disease that would not have been diagnosed without screening — and the complications of associated treatment.3 One approach to realizing the benefit of PSA screening while curtailing overdiagnosis is to administer a triage test in patients with . . .
TIL Therapy Entering the Mainstream
Authors: George Coukos
Journal: New England Journal of Medicine (2022)

Melanomas have long been considered to be immunogenic tumors. Although anti–programmed death 1 (PD-1) therapy has been approved worldwide as first-line treatment, many patients do not benefit from it, so there is an important therapeutic gap. Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) was described in the 1980s by Rosenberg and colleagues.1 This personalized treatment for cancer is based on the infusion of autologous T lymphocytes that have been obtained directly from surgically removed autologous tumors and then expanded in culture with the use of interleukin-2 stimulation. Both preconditioning lymphodepletion with high-dose, nonmyeloablative chemotherapy and the intravenous administration of high-dose . . .
Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select
Authors: Yiyuan Niu, Catarina A. Ferreira Azevedo, Xin Li, Elahe Kamali, Ole Haagen Nielsen, Claus Storgaard Sørensen, Morten Frödin
Journal: Nature Genetics (2022)

Abstract Determining the functional role of thousands of genetic sequence variants (mutations) associated with genetic diseases is a major challenge. Here we present clustered regularly interspaced short palindromic repeat (CRISPR)-Select TIME , CRISPR-Select SPACE and CRISPR-Select STATE , a set of flexible knock-in assays that introduce a genetic variant in a cell population and track its absolute frequencies relative to an internal, neutral control mutation as a function of time, space or a cell state measurable by flow cytometry. Phenotypically, CRISPR-Select can thereby determine, for example, pathogenicity, drug responsiveness/resistance or in vivo tumor promotion by a specific variant. Mechanistically, CRISPR-Select can dissect how the variant elicits the phenotype by causally linking the variant to motility/invasiveness or any cell state or biochemical process with a flow cytometry marker. The method is applicable to organoids, nontransformed or cancer cell lines. It is accurate, quantitative, fast and simple and works in single-well or 96-well higher throughput format. CRISPR-Select provides a versatile functional variant assay for research, diagnostics and drug development for genetic disorders.
Case 37-2022: A 55-Year-Old Man with Fatigue, Weight Loss, and Pulmonary Nodules
Authors: Matthew B. Roberts, Jarone Lee, Mark C. Murphy, Arthur Y. Kim, Erin E. Coglianese, Caroline Hilburn
Journal: New England Journal of Medicine (2022)

A 55-year-old man with a history of sarcoidosis was admitted 7 months after kidney transplantation for nephrocalcinosis because of fatigue, weight loss, and new pulmonary nodules. A diagnostic test was performed.
Second- and third-line treatment strategies in multiple myeloma: a referral-center experience
Authors: Sarah Goldman-Mazur, Alissa Visram, S. Vincent Rajkumar, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, Shaji K. Kumar
Journal: Blood Cancer Journal (2022)

The treatment landscape for relapsed multiple myeloma (MM) has increased. In this study, we aimed to characterize 2nd (n = 1439) and 3rd (n = 1104) line regimens and compare the results between subgroups based on the year of treatment initiation (2nd line: 2003-2008, 2009-2015, 2016-2021; 3rd line: 2004-2009, 2010-2015, and 2016-2021). In both the second- and third- lines, we observed increasing use of novel agents (from 78 to 95% and from 77 to 95%, respectively) and triplet regimens (from 15 to 69% and from 21 to 71%, respectively). The most frequently used regimens in the last studied periods included lenalidomide-dexamethasone (RD; 14%), carfilzomib-RD (12%), and daratumumab-RD (10%) for the second-line, and daratumumab-pomalidomide-dexamethasone (11%) and daratumumab-RD (10%) for the third-line. The median time to the next treatment from second-line therapy has improved from 10.4 months (95% CI: 8.4-12.4) to 16.6 months (95% CI: 13.3-20.3; p < 0.001). The median overall survival from the first relapse increased from 30.9 months (95% CI: 26.8-183.0) to 65.8 months (95% CI: 50.7-72.8; p < 0.001). Over the last two decades, more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and survival after the first relapse is continually improving.
NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications
Authors: Aaron Bodansky, Sara E. Vazquez, Janet Chou, Tanya Novak, Amer Al-Musa, Cameron Young, Margaret Newhams, Suden Kucukak, Laura D. Zambrano, Anthea Mitchell, Chung-Yu Wang, Kristin Moffitt, Natasha B. Halasa, Laura L. Loftis, Stephanie P. Schwartz, Tracie C. Walker, Elizabeth H. Mack, Julie C. Fitzgerald, Shira J. Gertz, Courtney M. Rowan, Katherine Irby, Ronald C. Sanders, Michele Kong, Jennifer E. Schuster, Mary A. Staat, Matt S. Zinter, Natalie Z. Cvijanovich, Keiko M. Tarquinio, Bria M. Coates, Heidi R. Flori, Mary K. Dahmer, Hillary Crandall, Melissa L. Cullimore, Emily R. Levy, Brandon Chatani, Ryan Nofziger, Raif S. Geha, Joseph DeRisi, Angela P. Campbell, Mark Anderson, Adrienne G. Randolph, Michele Kong, Ronald C. Sanders, Masson Yates, Chelsea Smith, Natalie Z. Cvijanovich, MattS. Zinter, Gwenn McLaughlin, Keiko M. Tarquinio, Bria M. Coates, Courtney M. Rowan, Adrienne G. Randolph, Margaret M. Newhams, Suden Kucukak, Tanya Novak, Hye Kyung Moon, Takuma Kobayashi, Jeni Melo, Cameron Young, Sabrina R. Chen, Janet Chou, Heidi R. Flori, Mary K. Dahmer, Emily R. Levy, Supriya Behl, Noelle M. Drapeau, Jennifer E. Schuster, Melissa L. Cullimore, Russell J. McCulloh, Shira J. Gertz, Stephanie P. Schwartz, Tracie C. Walker, Ryan A. Nofziger, Mary Allen Staat, Chelsea C. Rohlfs, Julie C. Fitzgerald, Elizabeth H. Mack, Nelson Reed, Natasha B. Halasa, Laura L. Loftis, Hillary Crandall
Journal: Journal of Allergy and Clinical Immunology (2022)
Emerging Strategies for the Treatment of Small Cell Lung Cancer
Authors: W. Jeffrey Petty, Luis Paz-Ares
Journal: JAMA Oncology (2022)

Importance Small cell lung cancer (SCLC) is an aggressive disease that is characterized by rapid growth and the early development of metastases. Patients typically respond to initial chemotherapy but quickly experience relapse, resulting in a poor long-term outcome. Therapeutic innovations that substantially improve survival have historically been limited, and reliable, predictive biomarkers are lacking. Observations This review examines the biologic characteristics of SCLC, the current treatment landscape, and ongoing efforts to identify novel therapeutic targets. Ongoing research has advanced the understanding of molecular categories and the immunologic microenvironment of SCLC, which in turn has helped improve disease classification and staging. Recently, immunotherapy-based regimens have become available for the management of SCLC, with 2 programmed cell death 1 ligand 1 inhibitors approved in combination with chemotherapy for first-line treatment of extensive-stage disease. For second-line treatment, a novel alkylating agent, lurbinectedin, which inhibits oncogenic transcription, has been approved for use in patients with metastatic SCLC. Furthermore, a wide variety of therapies and innovative combination regimens are being continuously evaluated. Potential therapeutic strategies, including aurora kinase A inhibitors, polyadenosine diphosphate-ribose polymerase inhibitors, ataxia telangiectasia and Rad3-related inhibitors, cyclin-dependent kinase 7 inhibitors, delta-like protein 3 agents, antiganglioside agents, CD47 inhibitors, and lysine-specific histone demethylase 1a inhibitors, are also being examined. Conclusions and Relevance Therapeutic optimization of SCLC remains a challenge, but recent trial results and drug approvals are encouraging. Advances in research have revealed critical information regarding biologic characteristics of the disease, which may lead to the identification of vulnerabilities and the development of new therapies. Further research focused on identifying biomarkers and evaluating innovative therapies will be paramount to improving treatment outcomes for patients with SCLC.
The mutational dynamics of short tandem repeats in large, multigenerational families
Authors: Cody J. Steely, W. Scott Watkins, Lisa Baird, Lynn B. Jorde
Journal: Genome biology (2022)

Abstract Background Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. Improving our understanding of these mutations would increase our knowledge of the mutational dynamics of the genome and may uncover additional loci that contribute to disease. To estimate the genome-wide pattern of mutations at STR loci, we analyze blood-derived whole-genome sequencing data for 544 individuals from 29 three-generation CEPH pedigrees. These pedigrees contain both sets of grandparents, the parents, and an average of 9 grandchildren per family. Results We use HipSTR to identify de novo STR mutations in the 2nd generation of these pedigrees and require transmission to the third generation for validation. Analyzing approximately 1.6 million STR loci, we estimate the empirical de novo STR mutation rate to be 5.24 × 10 −5 mutations per locus per generation. Perfect repeats mutate about 2 × more often than imperfect repeats. De novo STRs are significantly enriched in Alu elements. Conclusions Approximately 30% of new STR mutations occur within Alu elements, which compose only 11% of the genome, but only 10% are found in LINE-1 insertions, which compose 17% of the genome. Phasing these mutations to the parent of origin shows that parental transmission biases vary among families. We estimate the average number of de novo genome-wide STR mutations per individual to be approximately 85, which is similar to the average number of observed de novo single nucleotide variants.
Cohesin and CTCF control the dynamics of chromosome folding
Authors: Pia Mach, Pavel I. Kos, Yinxiu Zhan, Julie Cramard, Simon Gaudin, Jana Tünnermann, Edoardo Marchi, Jan Eglinger, Jessica Zuin, Mariya Kryzhanovska, Sebastien Smallwood, Laurent Gelman, Gregory Roth, Elphège P. Nora, Guido Tiana, Luca Giorgetti
Journal: Nature Genetics (2022)

In mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions.
Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation
Authors: Lasti Erfinanda, Lin Zou, Birgitt Gutbier, Laura Kneller, Sarah Weidenfeld, Laura Michalick, Disi Lei, Katrin Reppe, Luiz Gustavo Teixeira Alves, Bill Schneider, Qi Zhang, Caihong Li, Diana Fatykhova, Paul Schneider, Wolfgang Liedtke, Eisei Sohara, Timothy J. Mitchell, Achim D. Gruber, Andreas Hocke, Stefan Hippenstiel, Norbert Suttorp, Andrea Olschewski, Marcus A. Mall, Martin Witzenrath, Wolfgang M. Kuebler
Journal: Science Translational Medicine (2022)

Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after Streptococcus pneumoniae infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl-]i and [Ca2+]i). Inhibition of the chloride ion-sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [Ca2+]i, whereas WNK1 activation by temozolomide attenuated it. Endothelial [Ca2+]i transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in Trpv4 (Trpv4-/-) developed less lung edema and protein leak than their wild-type littermates after infection with S. pneumoniae. The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after S. pneumoniae infection in wild-type mice. In conclusion, lung infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.
A review on cell damage, viability, and functionality during 3D bioprinting
Authors: He-Qi Xu, Jia-Chen Liu, Zheng-Yi Zhang, Chang-Xue Xu
Journal: Military Medical Research (2022)

Abstract Three-dimensional (3D) bioprinting fabricates 3D functional tissues/organs by accurately depositing the bioink composed of the biological materials and living cells. Even though 3D bioprinting techniques have experienced significant advancement over the past decades, it remains challenging for 3D bioprinting to artificially fabricate functional tissues/organs with high post-printing cell viability and functionality since cells endure various types of stress during the bioprinting process. Generally, cell viability which is affected by several factors including the stress and the environmental factors, such as pH and temperature, is mainly determined by the magnitude and duration of the stress imposed on the cells with poorer cell viability under a higher stress and a longer duration condition. The maintenance of high cell viability especially for those vulnerable cells, such as stem cells which are more sensitive to multiple stresses, is a key initial step to ensure the functionality of the artificial tissues/organs. In addition, maintaining the pluripotency of the cells such as proliferation and differentiation abilities is also essential for the 3D-bioprinted tissues/organs to be similar to native tissues/organs. This review discusses various pathways triggering cell damage and the major factors affecting cell viability during different bioprinting processes, summarizes the studies on cell viabilities and functionalities in different bioprinting processes, and presents several potential approaches to protect cells from injuries to ensure high cell viability and functionality.
In vitro and in vivo evaluation of cerium oxide nanoparticles in respiratory syncytial virus infection
Authors: Akhil Patel, Jessica Kosanovich, Sameera Sansare, Sricharani Balmuri, Vinayak Sant, Kerry M. Empey, Shilpa Sant
Journal: Bioactive Materials (2022)

Respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis among children worldwide, yet there is no vaccine for RSV disease. This study investigates the potential of cube and sphere-shaped cerium oxide nanoparticles (CNP) to modulate reactive oxygen (ROS) and nitrogen (RNS) species and immune cell phenotypes in the presence of RSV infection in vitro and in vivo. Cube and sphere-shaped CNP were synthesized by hydrothermal and ultrasonication methods, respectively. Physico-chemical characterization confirmed the shape of sphere and cube CNP and effect of various parameters on their particle size distribution and zeta potential. In vitro results revealed that sphere and cube CNP differentially modulated ROS and RNS levels in J774 macrophages. Specifically, cube CNP significantly reduced RSV-induced ROS levels without affecting RNS levels while sphere CNP increased RSV-induced RNS levels with minimal effect on ROS levels. Cube CNP drove an M1 phenotype in RSV-infected macrophages in vitro by increasing macrophage surface expression of CD80 and CD86 with a concomitant increase in TNFα and IL-12p70, while simultaneously decreasing M2 CD206 expression. Intranasal administration of sphere and cube-CNP were well-tolerated with no observed toxicity in BALB/c mice. Notably, cube CNP preferentially accumulated in murine alveolar macrophages and induced their activation, avoiding enhanced uptake and activation of other inflammatory cells such as neutrophils, which are associated with RSV-mediated inflammation. In conclusion, we report that sphere and cube CNP modulate macrophage polarization and innate cellular responses during RSV infection.
Continuous glucose monitoring and metrics for clinical trials: an international consensus statement
Authors: Tadej Battelino, Charles M Alexander, Stephanie A Amiel, Guillermo Arreaza-Rubin, Roy W Beck, Richard M Bergenstal, Bruce A Buckingham, James Carroll, Antonio Ceriello, Elaine Chow, Pratik Choudhary, Kelly Close, Thomas Danne, Sanjoy Dutta, Robert Gabbay, Satish Garg, Julie Heverly, Irl B Hirsch, Tina Kader, Julia Kenney, Boris Kovatchev, Lori Laffel, David Maahs, Chantal Mathieu, Dídac Mauricio, Revital Nimri, Rimei Nishimura, Mauro Scharf, Stefano Del Prato, Eric Renard, Julio Rosenstock, Banshi Saboo, Kohjiro Ueki, Guillermo E Umpierrez, Stuart A Weinzimer, Moshe Phillip
Journal: The Lancet Diabetes & Endocrinology (2022)
Progress Toward Measles and Rubella Elimination — India, 2005–2021
Authors: Ratnesh Murugan, Kristin VanderEnde, Veena Dhawan, Pradeep Haldar, Sourabh Chatterjee, Deepa Sharma, Kevisetuo Anthony Dzeyie, Subramanya Balakuntlam Pattabhiramaiah, Sudhir Khanal, Lucky Sangal, Sunil Bahl, Sukarma S.S. Tanwar, Michelle Morales, Ahmed M. Kassem
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In 2019, India, along with other countries in the World Health Organization (WHO) South-East Asia Region,* adopted the goal of measles and rubella elimination by 2023,† a revision of the previous goal of measles elimination and control of rubella and congenital rubella syndrome (CRS) by 2020§ (1-3). During 2017-2021, India adopted a national strategic plan for measles and rubella elimination (4), introduced rubella-containing vaccine (RCV) into the routine immunization program, launched a nationwide measles-rubella supplementary immunization activity (SIA) catch-up campaign, transitioned from outbreak-based surveillance to case-based acute fever and rash surveillance, and more than doubled the number of laboratories in the measles-rubella network, from 13 to 27. Strategies included 1) achieving and maintaining high population immunity with at least 95% vaccination coverage by providing 2 doses of measles- and rubella-containing vaccines; 2) ensuring a sensitive and timely case-based measles, rubella and CRS surveillance system; 3) maintaining an accredited measles and rubella laboratory network; 4) ensuring adequate outbreak preparedness and rapid response to measles and rubella outbreaks; and 5) strengthening support and linkages to achieve these strategies, including planning and progress monitoring, advocacy, social mobilization and communication, identification and utilization of synergistic linkages of integrated program efforts, research, and development. This report describes India's progress toward the elimination of measles and rubella during 2005-2021, with a focus on the years 2017-2021.¶ During 2005-2021, coverage with the first dose of a measles-containing vaccine (MCV) administered through routine immunization increased 31%, from 68% to 89%. During 2011-2021, coverage with a second MCV dose (MCV2) increased by 204%, from 27% to 82%. During 2017-2021, coverage with a first dose of RCV (RCV1) increased almost 14-fold, from 6% to 89%. More than 324 million children received a measles- and rubella-containing vaccine (MRCV) during measles-rubella SIAs completed in 34 (94%) of 36 states and union territories (states) during 2017-2019. During 2017-2021, annual measles incidence decreased 62%, from 10.4 to 4.0 cases per 1 million population, and rubella incidence decreased 48%, from 2.3 to 1.2 cases per 1 million population. India has made substantial progress toward measles and rubella elimination; however, urgent and intensified efforts are required to achieve measles and rubella elimination by 2023.